The goal of this project is to develop improved methods for diagnosing and treating the ocular complications of the acquired immunodeficiency syndrome (AIDS). This project encompasses clinical trials evaluating new diagnostic and therapeutic approaches for patients with AIDS-related eye disorders, as well as natural history studies of patients with Cytomegalovirus (CMV) retinitis. Cytomegalovirus (CMV) retinitis is the most common intraocular infection in patients with AIDS and tends to occur after CD4+ cell counts decrease to less than 50 cells/?l. Although anti-CMV therapy with ganciclovir, foscarnet sodium, or cidofovir initially leads to inactivation of the retinitis, the disease progresses in almost all patients despite continued therapy because of inadequate control of the replicating virus. Recent studies have shown that treatment with highly active combination antiretroviral therapy, consisting of protease inhibitors and nucleoside analogs, has led to decreased human immunodeficiency virus (HIV) loads and increased CD4+ counts. We have been investigating the effect of immune restoration following combination anti-HIV therapy on CMV retinitis. We previously reported four patients with AIDS and increases in CD4+ cell counts induced by highly active combination antiretroviral chemotherapy who had persistently inactive CMV retinitis despite no specific anti-CMV medications. During the last year, we reported eight patients with CD4+ cell counts above 100 cells/?l and stable CMV retinitis after maintenance anti-CMV medications were discontinued. The NEI is now conducting a prospective clinical trial to determine whether maintenance anti-CMV medications can be safely discontinued in patients with stable retinitis. The study is also designed to determine whether discontinuing anti-CMV therapy will increase HIV load or cause intraocular inflammation. Recruitment of the initial phase of the trial has been completed, and data should be analyzed during the next year. In the second phase of the trial, we will continue to discontinue maintenance anti-CMV medications in patients with stable retinitis. In addition, we will perform leukopharesis and examine whether in vitro studies on lymphocytes can predict recurrence of retinitis. As part of this study, a heterodpulex assay will analyze the T cell receptor repertoire. Finally, many medications used to treat AIDS have ocular side effects. We first reported that the antiretroviral agent didanosine caused retinal toxicity. We have been using the electro-oculogram (EOG), which measures the electrical signal from the retina, to monitor the potentially toxic effect of didanosine on the retina in HIV-infected children. Currently, we are monitoring children in a Phase I protocol for the administration of a fluorinated analogue of didanosine in patients with HIV-associated diseases. Other medications with ocular side effects include rifabutin and cidofovir. We continue to perform periodic eye examinations on a cohort of both adults and children with AIDS to monitor patients for the development of ocular side effects in addition to opportunistic infections.